TW201540303A - Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to pharmaceutically acceptable complex formulae comprising complexes of Fulvestrant, or a salt, or derivatives thereof and pharmaceutically acceptable excipients, process for the preparation thereof and pharmaceutical compositions containing them. The complex formulae of the present invention have improved physicochemical properties which makes the compound orally available and makes oral administration of the compound possible in the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

Description

Complex of Farod and its derivatives, preparation process and pharmaceutical composition

The present invention relates to a stable complex having a controlled particle size, increased apparent solubility and increased dissolution rate, the complex comprising the active compound Fulvestrant, A salt or a derivative thereof is used in the treatment of a hormone receptor-positive metastatic breast cancer in a postmenopausal woman who has undergone anti-estrogen therapy after disease progression. More particularly, the complex of the present invention increases visual solubility, permeability, making the compound orally and enabling oral administration of the compound. The present invention also relates to a formulation method and a production method of a complex according to the present invention, a pharmaceutical composition comprising the same, a use thereof, and a treatment method using the same and a composition thereof.

The chemical name of Farod is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl)nonyl]estra-1,3,5-(10)-triene-3,17 beta-diol . The molecular formula is C ₃₂ H ₄₇ F ₅ O ₃ S, and its structural formula is:

Fallow is a white powder with a molecular weight of 606.77. The solution used for injection is a clear, colorless to yellow, viscous liquid.

Inactive ingredients contained in each injection: 10% w/v alcohol (Alcohol), United States Pharmacopoeia (USP), 10% w/v Benzyl Alcohol, official prescription ( NF) and 15% w/v Benzyl Benzoate, USP as co-solvents, and castor oil, USP as cosolvent and release rate modifier ) close to 100% w/v.

Many breast cancers have estrogen receptors (ER), and the growth of these tumors can be stimulated by estrogen. Farod is an estrogen receptor antagonist that binds to estrogen receptors in a competitive manner. Affinity is comparable to estradiol and downregulates human breast cancer cells. Estrogen receptor protein.

In vitro studies have demonstrated that the Fallowde is a reversible inhibitor of growth against tamoxifen-resistant and estrogen-sensitive human breast cancer (MCF-7) cell lines. In vivo in vivo studies, Farrow delayed the tumor establishment of xenografts in human breast cancer MCF-7 cells in nude mice. Fallowe inhibits the growth of established MCF-7 xenografts and breast tumor xenografts against tamoxifen.

Fulvestrant in immature or ovariectomized There is no agonist-type efficacy in in vivo uterotropic assays in (ovariectomized) mice or rats. In an in vivo study of immature and ovariectomized monkeys, Froude prevented the uterine promoting effect of estradiol. In postmenopausal women, the response to Froude treatment (250 mg per month) was unchanged in plasma concentrations of follicle stimulating hormone (FSH) and luteal growth hormone (LH), suggesting no peripheral steroidal effects (steroidal Effect).

After 250 mg of Farod's intramuscular administration, Farrow was slowly absorbed. The maximum plasma concentration was reached after approximately 7 days. Single dose studies have demonstrated continuous absorption for more than one month and terminal half-life for approximately 50 days. The variability of exposure after the first intramuscular (IM) long-acting (LA) dose was greater; the coefficient of variation (CV) was _25-70 % for AUC _{0-28d and 28-83} % for C _max . Dosing once a month results in approximately 2 to 3 fold accumulation. Stable state was reached after about 6 months, but a large amount of accumulation was obtained after 3 to 4 doses. In the steady state, the C _max /C _min ratio is ~2. A relatively low variability was observed at a steady state with a CV of ~15%.

Using research comparisons, bioavailability has been estimated as About 90-100%. In the range of 50 to 500 mg of the study, the exposure was approximately proportional to the dose.

After the 14C-labeled Farod muscle and intravenous administration, determine the body of Farrow Biological transformation and disposal. Farod's metabolism is characterized by a combination of several possible biotransformation pathways similar to endogenous steroids, including oxidation, aromatic hydroxylation, and steroid nucleus 2 3 and Binding of glucuronic acid and/or sulphate at position 17 and oxidation of the side chain sulphoxide. The identified metabolites either lack activity or exhibit activity similar to Farod in the anti-estrogen model.

Study on the use of human liver preparations and recombinant human enzymes It is indicated that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isozyme (isoenzyme) involved in the oxidation of Farod; however, P-450 and non-P-450 routes in vivo The relative contribution is not known.

Falod's use of excretion through the hepatobiliary route is mainly via feces. The speed is cleared (approximately 90%). Neglective exclusion (less than 1%) can be ignored. After an intramuscular injection of 250 mg, the clearance rate (mean standard deviation ± standard deviation) (Mean ± SD) was 690 ± 226 ml / min (mL / min), and the half-life of the appearance was about 40 days.

Due to poor solubility, Fallow is unable to achieve adequate oral bioavailability. Therefore, Farrow is developed to be administered by intramuscular injection. The development goal of Farod's intramuscular injection is to achieve efficient delivery of the active ingredient, using a formula to control the rate of drug input and to reduce the frequency of administration. Studies in the industry have been conducted to measure the solubility of faropenes in the range of oils, esters and alcohols for inclusion bodies in intramuscular injection formulations. It was found that castor oil together with a co-solvent (benzyl alcohol, ethanol and benzyl benzoate) is most suitable for allowing a Froude concentration of 50 mg/ml (mg/ml).

The main safety concern surrounding Froude injection is the intramuscular injection of the drug. Shoot. Care must be taken when using patients with bleeding disorders, reduced platelet counts, or patients receiving anticoagulants (eg, warfarin), in addition to pain at the injection site. Non-muscular injection of the drug will avoid all These concerns.

A further problem with the current formulation is that it needs to be performed twice in 1, 15, and 29 days. ML injections, one for each hip, and once a month thereafter. There is a problem with the pain associated with these injections.

Current intramuscular administration methods are limited by the volume of each injection (5 ml) The injection itself is limited by the solubility of Froude in castor oil and cosolvents. Froude's new complex form has greater visual solubility, allowing for a much smaller injection volume, perhaps allowing the number of injections to be reduced from 2 to 1 time.

Shortening the time to maximum plasma concentration ( _Cmax ) should theoretically allow more patients to reach therapeutic concentrations more quickly, which can result in increased response rates. Similarly, a decrease in the variability of _Cmax and area under the curve of the drug (AUC) also produces a better therapeutic effect.

To overcome the previous traditional Farod formula and the available drug delivery system A related problem, a novel complex formulation of Froude or its derivatives with stabilizers and pharmaceutically acceptable excipients is characterized by increased visual solubility, transient solubility, increased permeability, and compounds Oral, for the currently used intramuscular injection method, Faslodex achieves a possible alternative oral administration.

A variety of strategies have been used to try to overcome these problems, for example, please refer to WO2012035516, WO2013143300, WO2012160223, EP2249839, WO2011022861, WO2007069272, WO2009040818 and WO2009133418.

The present invention discloses a stable complex comprising an active compound selected from the group consisting of Fallow, its salts or a combination thereof, and at least one complexing agent selected from polyvinyl caprolactam-polyvinyl acetate. Polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymer, poloxamers, polyvinylpyrrolidone, vinylpyrrolidone and vinyl acetate -acetate copolymer, and a combination of poly(maleic acid-co-methyl-vinyl-ether), the complex is characterized by having the following Characteristics: a) instantaneous redispersibility in physiologically relevant media; b) solid form and colloidal solution and/or dispersion stabilization c) visual solubility in water at least 1 mg/ml; d) solid form X-ray amorphous Characteristics; e) Parallel artificial membrane permeation model permeability is at least when dispersed in a physiologically relevant medium of fast post-fast intestinal fluid (FaSSIF) or small intestinal intestinal fluid (FeSSIF) after at least one month 0.5 * ^10-6 Min / sec; F) characterized in that the infrared (ATR) spectrum of at least 1412 cm ^{-1 (-1} cm), ^{1197cm -1} having a master / and a characteristic absorption peak at 1105cm ^-1; and lack of 1611cm ^-1 and 1504cm ^-1 wherein Absorption spikes; and g) complexes can be taken orally.

The present invention is a complex formulation having increased visual solubility and permeability such that the compound can be administered orally as a currently used intramuscular formulation, Faslodex A possible alternative oral administration is achieved.

Only selected groups of stabilizers and pharmaceutically acceptable excipients disclosed herein The combination produces a stable complex formulation with improved physicochemical properties and enhanced biologic performance.

The expression Fulvestrant is usually used for Fulvestrant or salt classes such as Fulvestrant 3-Sulfate Sodium Salt or its derivatives.

In the examples, the complexing agent is selected from polyethylene glycol glyceride (polyethylene) A collection of glycol glycerides, polyethylene glycol glycerides consisting of mono-, di-, and triglycerides, as well as mono- and di-ester polyethylene glycols (eg, glyceryl ester 44/14 ( Gelucire 44/14), glyceride 50/13), hydroxypropylcellulose (eg Klucell EF, Klucell LF), poloxamer (copolymer of ethylene oxide and propylene oxide block) For example, Lutrol F127), vinylpyrrolidone/vinyl acetate copolymer (eg, Luviskol VA64), polyethylene glycol (eg, PEG2000, PEG6000), poly(2-ethyl-2- Oxazoline) (eg, PEOX50, PEOX500), polyvinylpyrrolidone (eg, Plasdone K-12, PVP 40, PVP K90, PVP 10), based on ethylene oxide and propylene oxide (eg Bulk copolymer of propylene oxide (for example, Pluronic PE10500, Pluronic PE6800, Pluronic F108), poly(maleic acid/methyl vinyl ether) (PMAMVE), polyethylene caprolactam-polyethylene-polyethylene glycol graft copolymer (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) (for example; S Oluplus), polyoxyl 15 hydroxystearate (eg; Solutol HS15), ethylene oxide/epoxy propylene block copolymer (eg; Tetronic 1107) Polyethylene glycol 1000 vitamin E succinate (d-alpha tocopheryl polyethylene glycol 1000 succinate) (TPGS) composition.

In the examples, the binder is a poloxamer (a nonionic polyethylene oxide-polyepoxy (propylene) alkane copolymer).

In the examples, this poloxamer is poloxamer 407 (Lutrol F127).

In an embodiment, the complex further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of sodium lauryl sulfate and sodium acetate.

In the examples, the pharmaceutically acceptable excipient is sodium acetate.

In the examples, the complex has a controlled particle size in the range between 50 nm and 600 nm. In the examples, the particle size is between 50 and 200 nm.

In an embodiment, the complex comprises a plurality of additional active agents.

In the examples, the additional active agent is selected from agents that are effective for hormone receptor positive metastatic breast cancer in postmenopausal women who have undergone disease progression after antiestrogen therapy.

In the examples, the additional active agent is selected from the group consisting of tamoxifen, letrozole, anastrozole, and combinations thereof.

In the examples, the complex has at least two of the properties described in a) to f).

In the examples, the complex has at least three of the properties described in a) to f).

In the examples, this complex has an increased rate of dissolution.

Further disclosed herein is a stable complex comprising an active compound selected from the group of Farod, a salt thereof or a derivative thereof; at least one complexing agent selected from the group B Alkenyl caprolactam-polyvinyl acetate-polyethylene-ethylene glycol graft copolymer, poloxamers, polyvinylpyrrolidone, vinylpyrrolidone and vinyl-acetate a copolymer, and a collection of poly(maleic acid-co-methyl-vinyl-ether); and at least one pharmaceutically acceptable excipient selected from sodium lauryl sulfate and sodium acetate, wherein the complex is by Obtained by a mixed process.

In the examples, the complexing agent is a poloxamer.

In the examples, this poloxamer is poloxamer 407 (Lutrol F127).

In the examples, the pharmaceutically acceptable excipient is sodium acetate.

In an embodiment, the complex is by a continuous flow mixing process. obtain.

In an embodiment, the complex comprises a poloxamer-based complexing agent and a pharmaceutical solution of sodium acetate Excipients are acceptable, and the total amount ranges from about 1.0 weight percent to about 95.0 weight percent, based on the total weight of the complex.

In the examples, the poloxamer's complexing agent and the pharmaceutically acceptable form of sodium acetate The agent comprises from about 50 weight percent to about 95 weight percent of the total weight of the complex.

This paper further discloses a preparation process for a complex, including the use of a water-soluble solution. A step of mixing a solution comprising a florol, a salt thereof or a derivative thereof in a pharmaceutically acceptable solvent, and a polyvinyl caprolactone-polyvinyl acetate-polyethylene-ethylene glycol Transplant copolymer, poloxamer; polyvinylpyrrolidone; copolymer of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl-ether) At least one intermixing agent selected, the aqueous solution comprising at least one pharmaceutically acceptable excipient selected from sodium lauryl sulfate and sodium acetate.

In an embodiment, the process is performed in a continuous flow instrument.

In an embodiment, the continuous flow instrument is a microfluidic flow instrument.

In the examples, the pharmaceutically acceptable solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, and combinations thereof. .

In the examples, the pharmaceutically acceptable solvent is n-propanol.

In the examples, the pharmaceutically acceptable solvent and the aqueous solution are mutually soluble.

In an embodiment, the aqueous solution comprises from 0.1 to 99.9% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50 to 90% by weight of the final solution.

In the examples, the aqueous solution comprises from 50 to 80% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50 to 70% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50 to 60% by weight of the final solution.

In the examples, the aqueous solution comprises 50% by weight of the final solution.

In an embodiment, the pharmaceutical composition comprises a complex as well as a pharmaceutically acceptable carrier.

In embodiments, the pharmaceutical composition is suitable for oral, pulmonary, rectal, colon, parenteral, intracisternal, intravaginal, intraperitoneal, eye, ear, local, Buccal, nasal or topical administration.

In the examples, the pharmaceutical composition is suitable for oral administration.

In the examples, the complex is used to make a drug for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women who have progressed after anti-estrogen therapy.

In the examples, the complex is used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women undergoing disease progression after antiestrogen therapy.

In an embodiment, a method of treating a hormone receptor-positive metastatic breast cancer in a post-menopausal woman undergoing disease progression after anti-estrogen therapy comprises administering a therapeutically effective amount of a complex or a pharmaceutical composition described herein .

In an embodiment, a method of reducing a therapeutically effective dose of Farrow, as compared to intramuscular injection, comprising oral administration of a pharmaceutical composition described herein.

Further disclosed herein is a stable complex comprising: a. 10 to 40% by weight of Fallow, its salts or derivatives thereof; b. 20 to 80% by weight of a poloxamer; and c. 5 ~50% by weight of sodium acetate, wherein the complex has a controlled particle size in the range between 500 nm and 600 nm; wherein the complex is not through a grinding process or through a high pressure homogenization process, packaging The process is obtained by a solid dispersion process, but is obtained by a mixing process, and is preferably a continuous flow mixing process.

In the examples, the particle size is between 50 nm and 200 nm.

In the examples, the poloxamer is poloxamer 407 (Lutrol F127).

In the examples, the complex was shown to reduce the effect of eating/fasting based on in vivo studies.

In the examples, the complex exhibited significantly increased exposure, earlier _tmax , higher _Cmax , allowing for oral administration and reduced dosage.

In the examples, this complex began to work faster than the existing intramuscular formulation.

In the examples, the complex is transiently redispersed in a physiologically relevant medium.

In the examples, the complex solid form and the colloidal solution and/or dispersion are stable.

In the embodiment, the complex has a visual solubility of at least 1 mg/ml in water; in the embodiment, the complex exhibits solid form X-ray amorphous characteristics; in the embodiment, when dispersed for at least 1 month, The complex has a parallel artificial membrane permeation model permeability of at least 0.5*10 ^-6 cm/sec when there is less time in the small intestine intestinal fluid (FaSSIF) or in the physiologically relevant medium after feeding small intestinal ileum (FeSSIF). .

In the examples, the complex is characterized by an infrared (ATR) spectrum having a dominant/characteristic absorption peak at at least 1412 cm ^-1 , 1197 cm ^-1 and 1105 cm ^-1 ; and a lack of characteristic absorption peaks of 1611 cm ^-1 and 1504 cm ^-1 .

Embodiments, the complexes further characterized in that the infrared spectrum at ^{1577cm -1, 1467cm -1, 1359cm -1} , 1343cm -1, 1281cm -1, 1242cm -1, 1146cm -1, 1060cm -1, 1012cm -1, ^{963cm -1, 924cm -1, 842cm -1} , 647cm -1 and at 619cm ^-1 master / absorption characteristic having peak.

The complexing agent and pharmaceutically acceptable excipient of the Froude's complex formulation of the present invention are selected from pharmaceutically acceptable nonionic, anionic, cationic, ionic polymers, surfactants and other types of excipients. set. The complexing agent itself, or together with a pharmaceutically acceptable excipient, can form a complex structure with an active pharmaceutical ingredient through non-covalent secondary interactions. Secondary interactions can be through electrostatic interactions such as ionic interactions, hydrogen bonding (H-bonding), dipoles - Dipole interaction, dipole-induced dipole interaction, London dispersive interaction, π-π interaction and hydrophobic interaction. The tweaking agent, pharmaceutically acceptable excipient, and active ingredient are selected from the group of complexing agents, pharmaceutically acceptable excipients, and active ingredients which are capable of forming such a complex structure through non-covalent secondary interactions.

In some embodiments, the composition additionally comprises one or more pharmaceutically acceptable forms Agent, auxiliary material, carrier, active agent or a combination thereof. In some embodiments, the active agent comprises an agent that is effective for the treatment of a hormone receptor-positive metastatic breast cancer in postmenopausal women who have progressed after anti-estrogen therapy.

Another aspect of the invention is a method having a complexing agent and a pharmaceutically acceptable excipient Lord's complex formula, in which the wrong agent and pharmaceutically acceptable excipients are associated or interacted with Farod, especially as a result of the mixing process, is the result of a continuous flow mixing process. In some embodiments, the structure of the complex Faraday formulation differs from the core-shell type abrasive particles, precipitated encapsulated particles, micelles, and solid dispersions.

The pharmaceutical composition of the present invention can be formulated as: (a) for oral administration, lung, a method of administration selected from the group consisting of rectal, colon, parenteral, cerebral cistern, intravaginal, intraperitoneal, ocular, auricular, topical, buccal, nasal and topical administration; (b) from liquid dispersions, gels a dosage form selected from the group consisting of aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) from controlled release formulations, ready-to-use formulations a delayed release formulation, an extended release, a pulsatile release formulation, and a selected dosage form of the combination of immediate release and controlled release formulations; or (d) (a), (b) and (c) random combination.

The composition can be formulated by adding different types of excipients for solidification Oral administration of body, liquid, topical (powder, ointment or drops) or topical administration.

The composition can be formulated by adding different types of pharmaceutically acceptable excipients. For oral administration in solid, liquid, topical (powder, ointment or drops) or topical administration.

Preferred dosage forms of the invention are in solid dosage form, but may be used arbitrarily Pharmaceutically acceptable dose.

Solid dosage forms for oral administration include, but are not limited to, capsules, Tablets, powders and granules. In these solid dosage forms, the active agent is admixed with at least one of: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; Fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose And silicic acid; (c) binders, such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) Humectants, such as glycerol; (e) disintegrating agents, such as crospovidon, sodium starch glycolate, effervescent compositions, cross-linked carboxylates Croscarmellose sodium, calcium carbonate, potato or tapioca starch, alginic acid, specific miscible citrate and sodium carbonate; (f) slow-release coagulant (solution retarders) ), such as C Acrylates, cellulose derivatives, paraffin; (g) absorption accelerators, such as quatemary ammonium compounds; (h) wetting agents, such as polysorbates, whales Cetyl alcohol and monostearate (glycerol monostearate); (i) adsorbents such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, stearic acid Magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage form can also contain a buffer.

In addition to these inert diluents, the compositions may also contain adjuvants such as wetting Agents, emulsifying and suspending agents, sweeteners, flavoring agents and aromatizing agents.

The advantages of the complex Faraday formulation of the present invention include, but are not limited to, (1) physical and chemical stability, (2) instantaneous redispersibility, (3) stability of the colloidal solution or dispersion at the treatment time window, (4) apparent solubility compared to the traditional Fallow recipe Increase, (5) increased permeability, (6) oral bioavailability, (7) reduced feeding/fasting effects, and (8) good processability.

The beneficial features of the invention are as follows: Froude's solid complex formulation in water, Good/instantaneous redispersibility in physiologically relevant media, such as physiological saline solution, hydrochloric acid solution at pH=2.5, intestinal intestinal fluid after feeding (FeSSIF) and fast intestinal intestinal fluid (FaSSIF) medium, and gastrointestinal fluid, and The stability of the colloidal solution and/or dispersion during the treatment time window.

One of the preferred properties of the complex Faraday formulation of the present invention is increased apparent solubility and permeability. In some embodiments, the complex Froude formula has an apparent solubility and permeability of at least 1 mg/ml and 0.5*10 ^-6 cm/sec, respectively.

Another preferred property of the complex Faraday formulation of the present invention is related to the addition Pharmacokinetic properties of the complex Farrow formula. The complex Farrow is orally available, enabling a possible alternative to oral administration of the currently used intramuscular formulation, Faslodex.

Figure 1 shows the screening agent for formulation selection to select formulations with transient redispersibility.

Figure 2 shows the comparative parallel artificial membrane permeation model (PAMPA) identification of a complex Fulvestrant formulation consisting of different pharmaceutically acceptable excipients.

Figure 3 shows the effect of the ratio of excipients associated with the material properties of the complex Farrow process formulation.

Figure 4 shows the effect of the ratio of excipients associated with the permeability of the parallel artificial membrane permeation model of the complex Farrowd formulation.

Figure 5 shows the particle size of the colloid solutions prepared at different flow rates and the particle size of the reconstituted solid complex Farrow formulation.

Figure 6 shows the particle size distribution of the re-dispersed solid complex of the synthetic colloidal solution and the selected formulation.

Figure 7 shows the effect of the flow rate ratio of the appearance of the solvent mixture after filtration on the active content.

Figure 8 shows the physical stability of the Froude formula monitored by filtration after the filtration to determine the Froude content of the colloidal solution.

Figure 9 shows the process enhancement effect of the redispersibility of the novel Froude formula.

Figure 10 shows a comparative dissolution test of a physical mixture of the complex Farrowd formulation with Farod, Lutrol F127 and sodium acetate.

Figure 11 shows the comparison of the complex artificial membrane permeation model of the complex Farrowd formula with the unformulated compound.

Figure 12 shows the stability of the colloidal solution in the simulated fasted and fed state.

Figure 13 shows the stability of the solid form detected when the parallel artificial membrane permeation model permeability was measured after redispersion in distilled water after storage under different conditions.

Figures 14A and 14B show scanning electron microscopy (SEM) photographs of the complex Farrow and stabilizer samples, respectively.

Figure 15 shows crystalline Farod (A), amorphous Farod (B), complex Farrow (C), stabilizer sample (D), poloxamer (Lutrol F127) (E) Attenuated total reflection (ATR) spectra with sodium acetate (F).

Figure 16 shows a powder X-ray diffraction pattern of the crystalline Fallowd and the complex Farrowd formulation.

Figure 17 shows the plasma concentrations after oral administration of the Fallowd complex according to the present invention to rats (n = 3) at a dose of 10 mg/kg (mg/kg) under fasting conditions.

Figure 18 shows the pharmacokinetic (PK) parameters produced after oral administration of the Fallowd complex according to the present invention to rats (n = 3) at a dose of 10 mg/kg under fasting conditions.

Figure 19 shows the plasma Faroe concentration of beagle dogs (11-13 kg, n=4) after oral administration of 20 mg of the complex Farrow in accordance with the present invention under fasted and fed conditions.

Figure 20 is a graph showing the pharmacokinetic (PK) parameters produced after oral administration of 20 mg of the complex Fallowd to beagle dogs (11-13 kg, n=4) in fasted and fed conditions.

As shown in Figure 1, a number of pharmaceutically acceptable complexing agents and pharmaceutically acceptable excipients and compositions thereof are tested to select a formulation having transient redispersibility. One of the examples of acceptable levels of redispersibility shown is selected for further analysis.

The permeability of the parallel artificial membrane permeation model of the selected formulation was measured to select the complex Fulvestrant formulation with optimal in vitro performance (see Figure 2). Parallel artificial membranes were completed as described by M. Kansi et al. (Journal of Medicinal Chemistry, 41, (1998), p. 1007) and according to the amendment of S. Bendels et al. (Pharmaceutical Research, 23 (2006), p. 2525). Permeability measurement of the infiltration model. An artificial membrane composed of a dodecane with 20% soy lecithin supported by a polyvinylidene fluoride (PVDF) membrane (Millipore, USA) Permeability was measured in the identification of well plates. The receiver compartment is phosphate buffered saline (pH 7.0) supplemented with 1% sodium dodecyl sulfate. The identification was completed at room temperature, and the incubation time was 1 to 24 hours. The concentration in the receptor pool was determined by UV-VIS spectrophotometry (Genesys S10 from Thermo Scientific).

Lutrol F127 as a cross-linking agent and as a pharmaceutically acceptable excipient Sodium acetate (excipients) was selected to form a complex Farrow formula with improved material properties.

The ratio of the selected miscible to the pharmaceutically acceptable excipient (Lutrol F127 to sodium acetate) was optimized and some slight differences were made during the preparation to correct some of the properties of the product. Farod's solid complexes were prepared using different ratios. Lutrol F127: The ratio of Farod is maintained at 0.5:1, 1:1 and 2:1, while the sodium acetate ratio in the composition is changed. Fixed sampling was redispersed in distilled water at the same concentration of 0.4 mg/ml of Froude. The Froude content after filtration of the redispersed solution (Fig. 3) and the permeability of the parallel artificial membrane permeation model (Fig. 4) were used to determine the composition of the complex Farrowod of the present invention (25 weight percent The most pharmaceutically acceptable excipients in Farod, 50% by weight of Lutrol F127 and 25% by weight of sodium acetate) Good ratio.

Glue of the Farrow's complex formulation having the optimum ratio of applied components of the present invention The bulk solution was prepared by continuous flow mixing in a flow instrument. As the starting solution, 200 mg of Fallowd and 400 mg of poloxamer (Lutrol F127) dissolved in 100 ml of n-propanol were used. The prepared solution was flowed into the apparatus at a flow rate of 2 ml/min (mL/min). Meanwhile, an aqueous solvent containing 250 mg of sodium acetate in 500 ml of water was flowed into the apparatus at a flow rate of 8 ml/min, and the complex Froude composition in the apparatus formed Farrow. The colloidal solution of the complex Farrow is continuously produced under atmospheric conditions. The resulting colloidal solution was frozen on dry ice and then lyophilized using a vacuum pump using a freeze drier equipped with a -110 ° C ice condenser. The monitoring process was used to monitor the particle size of the redispersed complex Froude formulation. The particle size of the colloidal solution prepared at different flow rates and the particle size of the reconstituted solid complex Faraday formulation can be seen in Figure 5. The stability of the reconstructed solid complex Froude formulation was monitored. Based on the physical appearance and stability of the reconstituted solid complex Froude formulation, the best composition was selected for analytical studies.

In order to make the production process industrially feasible, by increasing the concentration of the starting solution Degree, can complete the process enhancement. The colloidal solution of the Froude's complex formulation of the present invention was prepared by continuous flow mixing in a flow meter using enhanced process parameters. As a starting solution, 1400 mg of Fallowd dissolved in 100 ml of n-propanol and 2800 mg of poloxamer (Lutrol F127) were used. The prepared solution was flowed into the apparatus at a flow rate of 10 ml/min. Meanwhile, an aqueous solvent containing 1750 mg of sodium acetate in 500 ml of water was flowed into the apparatus at a flow rate of 40 ml/min, and the complex Froude composition in the apparatus formed Farrow.

Different flow ratios were tested to determine the best manufacturing conditions. Produced solvent mixture The appearance of the compound and the Froude content of the filtered solution mixture are used to determine the optimum parameters for production. Figure 7 summarizes these results. Based on these results, a flow ratio of 5 ml/min: 20 ml/min was selected for further optimization.

Depending on the optimized flow rate ratio (5:20), solvent blends containing the new Froude formula The compound was prepared and a solid formulation was prepared using a lyophilization method. The stability of the lyophilized powder was tested after one week of storage at 4 °C. The sampling system was reconstructed using purified water. The physical stability of the obtained milky white solution was also monitored in a timely manner by judging the Froude content of the filtered colloidal solution. The results are summarized in Figure 8.

Within the range of test accuracy, the results indicate that Froude, which has just been filtered after production The content is equivalent to the Froude content filtered after one week of storage. The Froude content of the filtrate is slightly reduced in a timely manner, but does not affect the appearance and redispersibility of the lyophilized powder.

Effect of process enhancement (process amplification) on in vitro properties

Process enhancements are also completed to increase production efficiency. The flow rate ratio increased from 5:20 to 10:40. The resulting solvent mixture is a solid formulation using a lyophilization process. The stability of the lyophilized powder was tested after one week of storage at 5 ± 3 °C. The sampling system was reconstructed using purified water. The physical stability of the obtained milky white solution was also monitored in a timely manner by judging the Froude content of the filtered colloidal solution. The results are summarized in Figure 9.

The results indicate that the enhancement of production does not correct the properties of the judgement material of the new Froude formula produced. The Froude content of the reconstituted filtrate of the new formulation prepared at different flow rates is nearly identical within the accuracy range. The results also show that the Froude content of the filtrate immediately after production is almost equivalent to the Froude content of the filtrate after one week of storage. The Froude content of the filtrate is slightly reduced in a timely manner, but does not affect the redispersibility and stability of the lyophilized powder. Based on these results, the flow rate ratio can be increased to 10 millimeters. L/min: 40 ml/min without loss of redispersibility and stability characteristics of the new formulation.

Comparative solubility test

The apparent solubility of the complex Farrowe formula and the unformulated compound was measured by ultraviolet visible spectroscopy at room temperature. The sample was dispersed in distilled water and the resulting dispersed solution was filtered through a 100 nm syringe filter. The active content of the filtrate was measured by UV-visible spectrophotometry and the solubility was calculated. The filtrate may contain Farrow's conjugate particles and cannot be filtered out using a 100 nm pore size filter.

The solubility of the complex Farrowe formula and the unformulated compound was 1.43 mg/ml and <0.03 mg/ml, respectively.

Comparative dissolution test

The physical solution of the complex Froude's formula with Farod, Lutrol F127 and sodium acetate was redispersed in purified water at a concentration of 0.25 mg/ml to complete a comparative dissolution test. After filtering at 0.45 micron pore size filters at different time points, the amount of dissolution was measured by ultraviolet-visible spectrophotometry. The Froude solution of the complex formulation dissolves instantaneously and fails to detect the Froude dissolution of the physical mixture (Fig. 10).

Comparison of in vitro parallel artificial membrane permeation models

Referring to Figure 11, the permeability of the parallel artificial membrane permeation model of the complex Farrow formula is greater than 0.6*10 ^-6 cm/s (cm/s) under simulated conditions of both fed and fasted states, while Formulated compounds are not detectable.

Stability of colloidal solution in the digestive tract (GI tract)

A simulation of the digestive tract is performed to detect any instability of the colloidal solution at pH values under fasting and eating conditions and the respective bile acid concentrations of the digestive tract. No view when simulating A significant change in light scattering of the colloidal solution was observed, indicating that the formulation was stable under these conditions in the time window of the absorption process under fasting and feeding conditions (Fig. 12).

Solid form stability

A stability test in solid form was performed. Parallel artificial membrane permeation model PAMPA permeability of solids was measured after storage under different conditions. Stored at -18 ° C, 4 ° C, room temperature (RT) or 40 ° C 75% relative humidity for 1 month, the figure shows that the PAMPA permeability of the parallel artificial membrane permeation model measured under any test conditions is not significantly reduced (Figure 13 ).

Structural analysis

The morphology of the complex Farrow was studied using FEI's Quanta 3D scanning electron microscope. The morphology of the complex of the present invention is compared to the sample preparation of the stabilizer prepared above, and the stabilizer sample contains sodium acetate and Lutrol F127, but lacks Fallow. The complex Farrow of the present invention consists of spherical particles (Fig. 14A). In the absence of the active compound, the pharmaceutically acceptable excipient does not form spherical particles (Fig. 14B).

Structural analysis was performed using Bruker's Vertex 70 Fourier Transform Infrared (FT-IR) spectrometer and Bruker's Platinum diamond Attenuated Total Reflection (ATR) unit. In the case of a selected pharmaceutically acceptable excipient such as poloxamer (Lutrol F127) and sodium acetate, the Froude is continuously flow-mixed to produce a stable complex of Farod. In a preferred embodiment of the complex or pharmaceutical composition of the present invention, the following characteristics are characterized by Raman or attenuated total reflection band/peak at least one (Fig. 15): 1577 cm ^-1 , 1467 cm ^{- 1, 1412cm -1, 1359cm -1,} 1343cm -1, 1281cm -1, 1242cm -1, 1197cm -1, 1146cm -1, 1105cm -1, 1060cm -1, 1012cm -1, 963cm -1, 924cm -1, 842cm ^-1, 647cm ^-1 and 619cm ^-1, at 1412cm ^-1, 1197cm ^-1 and 1105cm ^-1 preferred; or lack 1607 / 1611cm ^-1 absorption and 1501 / 1504cm ^-1 peaks.

The structure of the complex Farrow of the present invention was studied by a powder X-ray diffraction (XRD) analyzer (PW1050/1870 RTG powder diffractometer from Philips). The measurement results show that the complex Froude composition is XRD amorphous (please refer to Fig. 16). The characteristic reflection on the diffraction pattern of the complex Farrow is due to the sodium acetate in the formulation.

In vivo pharmacokinetics In vivo pharmacokinetic testing of small animals

After oral administration of the compound Froude formula in fasted rats, the highest plasma concentration was tested at the first time point (15 minutes), indicating that the absorption of the activity was very fast, similar to intravenous administration (Fig. 17). . Since there is no reference formulation available for control, relative bioavailability cannot be calculated, however, absorption/elimination profiles such as veins allow estimation of pharmacokinetic properties in rats (n=3), please refer to Figure 18. The compounds exhibited a very high volume of distribution, so in order to estimate the pharmacokinetic parameters, the later time points (1.5-8 hours) were used. Interestingly, at this dose level, the _Cmax value is approximately 5-10 times greater than the human therapeutic plasma concentration.

In vivo pharmacokinetic testing of large animals

The study of the beagle was done using a powder in a 20 mg bottle formulation under fasting and eating conditions (Fig. 19). The formulation is administered as a reconstituted colloidal solution. The API absorbs very quickly and reaches the _tmax value at 1 hour. The differences between individuals are small. Under fed conditions, the food had a slight effect, _{cmax was} lower, but the exposure was essentially the same. The clearance rate (estimated by t _1/2 ) was even higher than in rats (t _1/2 = 1.54 hours) (Fig. 20).

Although the embodiments of the present invention are disclosed above, it is not intended to limit the present invention, and those skilled in the art, regardless of the spirit and scope of the present invention, the shapes, configurations, and features described in the scope of the present application. And the number of modifications may be made, and the scope of patent protection of the present invention shall be determined by the scope of the patent application attached to the specification.

Claims (17)

A stable complex comprising an active compound selected from the group consisting of Farod, a salt thereof or a combination thereof, and at least one complexing agent selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene - Polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymer, poloxamers, polyvinylpyrrolidone, vinylpyrrolidone and vinyl-acetate a copolymer, and a combination of poly(maleic acid-co-methyl-vinyl-ether), which is characterized by having the following characteristics: a Instantly redispersible in physiologically relevant media; b) increased dissolution rate; c) solid form and colloidal solution and/or dispersion stable; d) visual solubility in water at least 1 mg/ml; e) solid form X-ray Amorphous characteristics; f) Parallel artificial membrane permeation model infiltration when dispersed in a physiologically relevant medium of fast intestinal intestinal fluid (FaSSIF) or small intestinal intestinal fluid (FeSSIF) after at least one month of inactivity Sex is at least 0.5 *10 ^-6 cm/sec; g) characterized by infrared (ATR) spectra with dominant/characteristic absorption peaks at at least 1412 cm ^-1 , 1197 cm ^-1 and 1105 cm ^-1 ; and lack of characteristic absorption peaks of 1611 cm ^-1 and 1504 cm ^-1 And h) the complex is orally bioavailable. The stable complex according to claim 1, wherein the complexing agent is selected from the group of polyethylene glycol glycerides, and the polyethylene glycol glyceride is mono-, di-, and triglyceride. Polyglycerides and mono- and di-ester polyethylene glycols (eg, glyceride 44/14 (Gelucire 44/14), glyceride 50/13), hydroxypropylcellulose (hydroxypropylcellulose) For example, Klucell EF, Klucell LF), poloxamer (copolymer of ethylene oxide and propylene oxide block) (for example, Lutrol F127), vinylpyrrolidone/vinyl acetate copolymerization (eg, Luviskol VA64), polyethylene glycol (eg, PEG2000, PEG6000), poly(2-ethyl-2-oxazoline) (eg, PEOX50, PEOX500), polyvinylpyrrolidone (eg, povidone) K-12, PVP 40, PVP K90, PVP 10), block copolymers based on ethylene oxide and propylene oxide (for example, Pluronic PE10500, Pluronic PE6800, Pluronic F108), poly ( Maleic acid/methyl vinyl ether) (PMAMVE), polyethylene caprolactam-polyethylene-polyethylene Alcohol graft copolymer (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) (e.g.; Soluplus), polyethylene glycol 15 hydroxystearate (polyoxyl 15 Hydroxystearate) (eg; Solutol HS15), ethylene oxide/epoxy propylene block copolymer (eg; Tetronic 1107) and d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) The composition is preferably a poloxamer. The stable complex according to claim 1 or 2, wherein the complex further comprises at least one pharmaceutically acceptable form selected from the group consisting of sodium-lauryl-sulfate and sodium acetate. The pharmaceutically acceptable excipient is preferably sodium acetate. The stable complex of any one of claims 1 to 3, wherein the complex further comprises one or more additional active agents selected from the group after treatment with antiestrogen therapy Preferably, a set of effective agents for hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression is selected from the group consisting of tamoxifen, letrozole and anastrozole ( The collection of anastrozole) is better. A stable complex according to any one of claims 1 to 4, which comprises an active compound selected from the group consisting of Farod, a salt thereof or a derivative thereof; at least one complexing agent selected from the group consisting of Vinyl caprolactam-polyvinyl acetate-polyethylene-ethylene glycol graft copolymer, poloxamer, polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate, and poly(maleic acid-co) a collection of -methyl-vinyl-ether; and at least one pharmaceutically acceptable excipient selected from sodium lauryl sulfate and sodium acetate, wherein the complex is obtained by a mixing process by continuous flow The mixing process is better, and the flow mixing process with microfluidics is better. A stable complex according to any one of claims 1 to 5, comprising a conjugate agent of poloxamer and a pharmaceutically acceptable excipient of sodium acetate, based on the total weight of the complex, The total amount ranges from about 1.0 weight percent to about 95.0 weight percent. A process for preparing a stable complex according to any one of claims 1 to 6, comprising the step of mixing a solution with an aqueous solution comprising a pharmaceutically acceptable solvent of Fallow, a salt thereof or a derivative thereof, and a copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene-ethylene glycol graft copolymer, poloxamer; polyvinylpyrrolidone; vinylpyrrolidone and vinyl acetate; And at least one complexing agent selected from the group of poly(maleic acid-co-methyl-vinyl-ether), wherein the aqueous solution comprises at least one pharmaceutically acceptable excipient selected from sodium lauryl sulfate and sodium acetate. The preparation process of claim 7, wherein the process is performed in a continuous flow instrument, preferably in a microfluidic instrument. The preparation process according to claim 7 or 8, wherein the pharmaceutically acceptable solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxide. A collection of tetrahydrofuran and combinations thereof, preferably a pharmaceutically acceptable solvent of n-propanol. The preparation process of any of claims 7 to 9, wherein the solution and the aqueous solution are mutually soluble, and the aqueous solution comprises a final solution of 0.1 to 99.9% by weight. A pharmaceutical composition comprising a stable complex as described in any one of claims 1 to 6 together with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is suitable for oral administration, lung, rectum, colon, parenteral, cerebral cistern, intravaginal, intraperitoneal, ocular, ear, topical, buccal, nasal or topical For administration, the pharmaceutical composition is preferably administered orally. A stable complex according to any one of claims 1 to 6 for use in the manufacture of a medicament for the treatment of hormone receptor-positive metastasis in postmenopausal women undergoing disease progression after anti-estrogen therapy Breast cancer. A use of a stable complex according to any one of claims 1 to 6 for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women undergoing disease progression after anti-estrogen therapy. A method of treating hormone receptor-positive metastatic breast cancer in postmenopausal women after anti-estrogen therapy, comprising a stable complex as described in any one of claims 1 to 6 or as claimed in claim 11 or The administration of a therapeutically effective amount of the pharmaceutical composition of 12. A method of reducing a therapeutically effective dose of a Froude compared to intramuscular injection, the method comprising the oral administration of the pharmaceutical composition of claim 11 or 12. A stable complex comprising: a) 10 to 40% by weight of Falod, a salt thereof or a derivative thereof; b) 20 to 80% by weight of a poloxamer; c) 5 to 50% by weight of sodium acetate, wherein the complex has a controlled particle size in the range between 500 nm and 600 nm, and the particle size is preferably between 50 nm and 200 nm. And wherein the complex is obtained by the preparation process as described in any one of claims 7 to 10.